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Last update 08 May 2025

SGPL1

Last update 08 May 2025

Basic Info

Synonyms

hSPL, KIAA1252, S1PL

+ [6]

Introduction

Cleaves phosphorylated sphingoid bases (PSBs), such as sphingosine-1-phosphate, into fatty aldehydes and phosphoethanolamine. Elevates stress-induced ceramide production and apoptosis (PubMed:11018465, PubMed:14570870, PubMed:24809814, PubMed:28165339). Required for global lipid homeostasis in liver and cholesterol homeostasis in fibroblasts. Involved in the regulation of pro-inflammatory response and neutrophil trafficking. Modulates neuronal autophagy via phosphoethanolamine production which regulates accumulation of aggregate-prone proteins such as APP (By similarity). Seems to play a role in establishing neuronal contact sites and axonal maintenance (By similarity).

Drugs associated with SGPL1

LX-2931

Target

SGPL1

Mechanism

SGPL1 inhibitors

Active Org.

AC BioScience SA

Originator Org.

Lexicon Pharmaceuticals, Inc.

Active Indication

Pancreatic Cancer [+2]

Inactive Indication

Darier Disease [+2]

Drug Highest PhasePhase 2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CN116531406

Patent Mining

Target

SGPL1

Mechanism-

Active Org.

Tian Qing Stem Cell Co., Ltd.

Originator Org.

Tian Qing Stem Cell Co., Ltd.

Active Indication

Endocrinology and Metabolic Disease

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

WO2023015189

Patent Mining

Target

SGPL1

Mechanism-

Active Org.

The Regents of the University of California

Originator Org.

The Regents of the University of California

Active Indication

Respiratory Diseases

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with SGPL1

EUCTR2018-000373-80-FR

/ Not yet recruitingPhase 1/2

A Phase 1/2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm Study of the Safety and Efficacy of LX3305, a Sphingosine-1-Phosphate Lyase Inhibitor, for Treatment of Darier’s Disease or Hailey-Hailey Disease - DERM-101

Start Date24 May 2018

Sponsor / Collaborator

Dermecular Therapeutics, Inc.

NCT01417052

/ CompletedPhase 1

A Phase 1, Single-Center, Randomized, Double-Blind, Placebo-Controlled, Dose Escalation Study to Determine the Safety and Efficacy of Daily Orally Administered LX3305 in Subjects With Active Rheumatoid Arthritis (RA)

The primary objective of this study is to determine the safety of LX3305 in a dose escalation compared with placebo over 12 weeks in subjects with active rheumatoid arthritis (RA).

Start Date01 Sep 2011

Sponsor / Collaborator

Lexicon Pharmaceuticals, Inc.

EUCTR2009-012705-19-BG

/ Not yet recruitingNot Applicable

A Phase 2, Multi-center, Randomized, Double-blind, Placebo-controlled, Multiple-dose Study to Determine the Safety and Efficacy of Daily Orally Administered LX3305 in Subjects with Active Rheumatoid Arthritis (RA) on Stable Methotrexate (MTX) Therapy - LX3305.201

Start Date29 Sep 2009

Sponsor / Collaborator

Lexicon Pharmaceuticals, Inc.

100 Clinical Results associated with SGPL1

100 Translational Medicine associated with SGPL1

0 Patents (Medical) associated with SGPL1

351

Literatures (Medical) associated with SGPL1

07 Jan 2025·Proceedings of the National Academy of Sciences

Molecular basis of Spns1-mediated lysophospholipid transport from the lysosome

Article

Author: Schmiege, Philip ; Li, Xiaochun ; Ha, Hoa T. T. ; Nguyen, Long N. ; Chen, Hongwen ; Le, Nhung A. ; Elghobashi-Meinhardt, Nadia

Spns1 mediates the rate-limiting efflux of lysophospholipids from the lysosome to the cytosol. Deficiency of Spns1 is associated with embryonic senescence, as well as liver and skeletal muscle atrophy in animal models. However, the mechanisms by which Spns1 transports lysophospholipid and proton sensing remain unclear. Here, we present a cryogenic electron microscopy structure of human Spns1 in lysophosphatidylcholine (LPC)-bound lumen-facing conformation. Notably, LPC snugly binds within the luminal-open cavity, where the molecular dynamics simulations reveal that LPC presents a propensity to enter between transmembrane-helices (TM) 5 and 8. Structural comparisons and cell-based transport assays uncover several pivotal residues at TM 5/8 that orchestrate the transport cycle, which are unique to Spns1. Furthermore, we identify a five-residue network that is crucial for proton-sensing by Spns1. Transference of these network residues to Spns2, a sphingosine-1-phosphate uniporter, causes the chimeric Spns2 to be low pH dependent. Our results reveal molecular insights into lysosomal LPC transport and the proton-sensing mechanism by Spns1.

01 Jan 2025·Journal of Neurochemistry

Deciphering the role of sphingosine 1‐phosphate in central nervous system myelination and repair

Review

Author: Xiao, Junhua ; Binish, Fatima

AbstractSphingosine 1‐phosphate (S1P) is a bioactive lipid of the sphingolipid family and plays a pivotal role in the mammalian nervous system. Indeed, S1P is a therapeutic target for treating demyelinating diseases such as multiple sclerosis. Being part of an interconnected sphingolipid metabolic network, the amount of S1P available for signalling is equilibrated between its synthetic (sphingosine kinases 1 and 2) and degradative (sphingosine 1‐phosphate lyase) enzymes. Once produced, S1P exerts its biological roles via signalling to a family of five G protein‐coupled S1P receptors 1–5 (S1PR1–5). Despite significant progress, the precise roles that S1P metabolism and downstream signalling play in regulating myelin formation and repair remain largely opaque and somewhat controversial. Genetic or pharmacological studies adopting various model systems identify that stimulating S1P‐S1PR signalling protects myelin‐forming oligodendrocytes after central nervous system (CNS) injury and attenuates demyelination in vivo. However, evidence to support its role in remyelination of the mammalian CNS is limited, although blocking S1P synthesis sheds light on the role of endogenous S1P in promoting CNS remyelination. This review focuses on summarising the current understanding of S1P in CNS myelin formation and repair, discussing the complexity of S1P–S1PR interaction and the underlying mechanism by which S1P biosynthesis and signalling regulates oligodendrocyte myelination in the healthy and injured mammalian CNS, raising new questions for future investigation.

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01 Dec 2024·Advances in Biological Regulation

Sphingosine phosphate lyase insufficiency syndrome as a primary immunodeficiency state

Review

Author: Saygili, Seha ; Mathew, Georgie ; Wright, Nicola.A.M. ; Saba, Julie D. ; Wright, NicolaA.M. ; Makkoukdji, Nadia ; Murguia-Favela, Luis ; Midgley, Julian ; Gans, Melissa ; Lesmana, Harry ; Eshleman, Juliette ; Wright, NicolaA M ; Murguila-Favela, Luis ; Gharagozlou, Saber ; Saba, Julie D

Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a genetic disease associated with renal, endocrine, neurological, skin and immune defects. SPLIS is caused by inactivating mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). SPL catalyzes the irreversible degradation of the bioactive sphingolipid sphingosine-1-phosphate (S1P), a key regulator of lymphocyte egress. The SPL reaction represents the only exit point of sphingolipid metabolism, and SPL insufficiency causes widespread sphingolipid derangements that could additionally contribute to immunodeficiency. Herein, we review SPLIS, the sphingolipid metabolic pathway, and various roles sphingolipids play in immunity. We then explore SPLIS-related immunodeficiency by analyzing data available in the published literature supplemented by medical record reviews in ten SPLIS children. We found 93% of evaluable SPLIS patients had documented evidence of immunodeficiency. Many of the remainder of cases were unevaluable due to lack of available immunological data. Most commonly, SPLIS patients exhibited lymphopenia and T cell-specific lymphopenia, consistent with the established role of the S1P/S1P1/SPL axis in lymphocyte egress. However, low B and NK cell counts, hypogammaglobulinemia, and opportunistic infections with bacterial, viral and fungal pathogens were observed. Diminished responses to childhood vaccinations were less frequently observed. Screening blood tests quantifying recent thymic emigrants identified some lymphopenic SPLIS patients in the newborn period. Lymphopenia has been reported to improve after cofactor supplementation in some SPLIS patients, indicating upregulation of SPL activity. A variety of treatments including immunoglobulin replacement, prophylactic antimicrobials and special preparation of blood products prior to transfusion have been employed in SPLIS. The diverse immune consequences in SPLIS patients suggest that aberrant S1P signaling may not fully explain the extent of immunodeficiency. Further study will be required to fully elucidate the complex mechanisms underlying SPLIS immunodeficiency and determine the most effective prophylaxis against infection.

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SGPL1

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